The present invention relates to a process for the preparation and purification of (RR,SS)-2-(dimethylamino)methyl!-1-(3-methoxyphenyl)cyclohexanol and its salts. More particularly, the present invention relates to an improved process for the purification and isolation of (RR,SS)-2-(dimethylamino)methyl!-1-(3-methoxyphenyl)cyclohexanol and its salts from reaction mixtures containing the (RR,SS) isomer, the (RS,SR) isomer, and Grignard reaction side products.
The hydrochloride salt of (RR,SS)-2-(dimethylamino)methyl!-1-(3-methoxyphenyl)cyclohexanol is commonly known as Tramadol. Tramadol is considered a non-addicting analgesic, and is indicated for the management of moderate to moderately severe pain.
The original preparation, isolation and purification of Tramadol was reported in Arzneimittel-Forsch./Drug Res. 28(I), Heft 1a, 107,114 (1978), and patented in British Patent 997,399 and U.S. Pat. No. 3,652,589. In this work, the compound is initially obtained from a Grignard reaction mixture as a mixture of the cis and the trans hydrochloride salts. The unwanted trans isomer is removed from the mixture by refluxing a slurry of this salt in wet dioxane, filtering while still hot, and repeating the procedure in anhydrous dioxane. A second filtration resulted in pure cis Tramadol hydrochloride. A disadvantage with this procedure results from the use of large quantities of dioxane. Dioxane has been listed as a carcinogen by the EPA, and has been linked to CNS depression and necrosis of the liver and kidneys.
Improved methods for separation of the cis and trans isomers have been described in two recent patent documents, both owned by Chemagis Ltd., of Bnei Brak, Israel. In the first of these, namely U.S. Pat. No. 5,414,129, the cis and trans isomers are separated from a Grignard reaction mixture by adding HCl (aqueous or anhydrous) to the crude reaction mixture in an organic solvent. This separation takes advantage of the selective precipitation of the cis (RR,SS) isomer from the reaction solution at a faster rate than the trans (RS,SR) isomer. According to the patent, a purity of 97.8% of the cis isomer is obtained after two recrystallizations. However, this indicates that over 2% of trans isomer remains. Furthermore, as stated in the later-published European Patent Application EP 0 778 262 (also owned by the assignee of the '129 patent), the process described in the '129 patent suffers from the disadvantage that the time interval between the end of separation of the (RR,SS) isomer and the start of the (RS,SR) isomer separation is variable, and seems to depend sharply on the composition of the crude mixture. Thus, according to the published European Patent Application, the yield and quality of the final product obtained from the purification process taught in the '129 patent may vary, and about 40% of the (RR,SS) isomer does not separate and remains in solution with the (RS,SR) isomer.
The process described in the European Patent Application EP 0 778 262 filed by Chemagis Ltd. uses a strong acid in an organic or aqueous medium to selectively dehydrate the (RS,SR) isomer, while the (RR,SS) isomer remains intact. The (RS,SR) isomer remains in the mother liquor upon crystallization of an amine salt of the (RR,SS) isomer. In this process, some of the trans (RS,SR) isomer is also converted to the cis (RR,SS) isomer. Yield losses have been found to be high with this process.
A reader should bear in mind that in the foregoing references of European origin, Tramadol is referred to as the trans isomer. However, when named according to IUPAC rules, Tramadol is the cis isomer. The present patent document follows IUPAC nomenclature rules, and thus, Tramadol is referred to herein as the cis isomer.
The known methods for preparation and/or purification of Tramadol suffer from significant disadvantages. For example, some methods use hazardous raw materials. Other methods require numerous steps, including multiple recrystallizations in order to obtain the desired product. Still other methods suffer from low yield, and low selectivity of the desired cis isomer.
Accordingly, it is desired to provide an improved process for the preparation and purification of (RR,SS)-2-(dimethylamino)methyl!-1-(3-methoxyphenyl)cyclohexanol and its salts that uses generally safe ingredients, is highly selective for the desired cis isomer, and provides high yield of the desired end product.